Single Mild Traumatic Brain Injury Research Articles

Long-Term Impact of Diffuse Traumatic Brain Injury on Neuroinflammation and Catecholaminergic Signaling: Potential Relevance for Parkinson's Disease Risk.

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson's disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou's impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate-severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DβH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

Role of brain metabolites during acute phase of mild traumatic brain injury in prognosis of post-concussion syndrome: A 1H-MRS study

This study has investigated the potency and accuracy of early magnetic resonance spectroscopy (MRS) to predict post-concussion syndrome (PCS) in adult patients with a single mild traumatic brain injury (mTBI) without abnormality on a routine brain scan. A total of 48 eligible mTBI patients and 24 volunteers in the control group participated in this project. Brain MRS over regions of interest (ROI) and signal stop task (SST) were done within the first 72 hours of TBI onset. After six months, PCS appearance and severity were determined. In non-PCS patients, N-acetyl aspartate (NAA) levels significantly increased in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to the control group, however, this increase of NAA levels were recorded in all ROI versus PCS subjects. There were dramatic declines in creatinine (Cr) levels of all ROI and a decrease in choline levels of corpus callosum (CC) in the PCS group versus control and non-PCS ones. NAA and NAA/Cho values in ACC were the main predictors of PCS appearance. The Cho/Cr level in ACC was the first predictor of PCS severity. Predicting accuracy was higher in ACC than in other regions. This study suggested the significance of neuro-markers in ACC for optimal prediction of PCS and rendered a new insight into the biological mechanism of mTBI that underpins PCS.

A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

Short-term behavioral and histological changes in a rodent model of mild traumatic brain injury

An in-house developed weight drop injury (WDI) device is a recently described animal model of traumatic brain injury (TBI) that was designed to produce a blunt, closed-head injury. More specifically, the apparatus was designed to reliably generate a wide range of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of a single mild TBI (mTBI) impact using our WDI device by characterizing the relationship between the biomechanical input and the behavioral and histological inflammatory outcomes. Rats were subjected to a single mTBI impact using two impact energies of 0.2 and 0.5J, and post-impact outcomes were assessed over two recovery periods of 3- and 7-days. Here we report that a single, closed-head impact energy of 0.5J and below produces no significant phenotype. Despite the insignificant results of alterations in behavior and inflammatory analysis, the study revealed important aspects of lower-level impact loads. First, this work provides evidence in support of the notion that not every closed-head impact has the capacity to result in system perturbations. Although a theoretical injury threshold may not exist for rats using a WDI model, we hypothesize a biomechanical threshold of impact associated with a lack of functional impairment and neuroinflammation due to a single closed-head injury is likely around an energy level of 0.5 J.

Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury

Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.

Diverse changes in microglia morphology and axonal pathology during the course of 1year after mild traumatic brain injury in pigs.

Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long‐term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1‐year post‐injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1‐year post‐injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.

Social Support Buffers Against Cognitive Decline in Single Mild Traumatic Brain Injury With Loss of Consciousness: Results From the Canadian Longitudinal Study on Aging.

We investigated rates of cognitive decline at 3-year follow-up from initial examination in people reporting mild traumatic brain injury (mTBI) with loss of consciousness (LOC) more than a year prior to initial examination. We examined the role of social support as predictor of preserved cognitive function in this sample. Analyses were conducted on 440 participants who had self-reported LOC of <1 min, 350 with LOC of 1-20 min, and 10,712 healthy controls, taken from the Canadian Longitudinal Study on Aging (CLSA), a nationwide study on health and aging. People who reported at baseline that they had experienced mTBI with LOC of 1-20 min more than a year prior were 60% more likely to have experienced global cognitive decline than controls at three-year follow-up. Cognitive decline was most apparent on measures of executive functioning. Logistic regression identified increased social support as predictors of relatively preserved cognitive function. mTBI with longer time spent unconscious (i.e., LOC 1-20 min) is associated with greater cognitive decline years after the head injury. Perceived social support, particularly emotional support, may help buffer against this cognitive decline.

Subtle long-term cognitive effects of a single mild traumatic brain injury and the impact of a three-month aerobic exercise intervention.

Although there is a growing body of literature on the impact of multiple concussions on cognitive function with aging, less is known about the long-term impact of sustaining a single mild traumatic brain injury (mTBI). Additionally, very few interventions exist to treat mTBI patients and prevent a possible accelerated cognitive decline. This study aimed to: 1) examine the long-term effects of a single mTBI on cognition in patients aged between 55 and 70 years old; and 2) evaluate the cognitive effects of an aerobic exercise program for these patients. Thirty-five participants (average age: 58.89, SD=4.14) were assessed using neuropsychological tests. Among them, 18 hadsustained a mTBI two to seven years earlier. Significant differences in information processing speed, executive function and visual memory were found between controls and mTBI patients. Sixteen of the mTBI patients then engaged in a 12-week physical exercise program. They were divided into equivalent groups: 1) aerobic training (cycle ergometers); or 2) stretching exercises. The participants' cardiopulmonary fitness (VO<inf>2max</inf>) was evaluated pre- and postintervention and neuropsychological tests were re-administered postintervention. Participants from the aerobic group significantly improved their fitness compared to the stretching group. However, no between-group difference was found on neuropsychological measures postintervention. In summary, this study shows long-term cognitive effects of mTBI in late adulthood patients. Moreover, the controlled, 12-week aerobic exercise program did not lead to cognitive improvements in our small mTBI sample. Lastly, future directions in optimizing mTBI intervention are discussed.

Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats.

While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behavior and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks and were periodically tested for changes in motor behavior, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behavior, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment, and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

Long-term cognitive impairment following single mild traumatic brain injury with loss of consciousness: Findings from the Canadian Longitudinal Study on Aging

ABSTRACTObjective: We examined the extent to which loss of consciousness (LOC) following mild traumatic brain injury (mTBI) may be associated with impairments in executive functions and declarative memory more than a year after brain injury.Method: Analyses were run on 548 participants who had self-reported LOC of <1 min, 441 with LOC of 1–20 min, and 13,609 no brain injury comparison participants, taken from the Canadian Longitudinal Study on Aging (CLSA), a nationwide study on health and aging.Results: Those that had mTBI with LOC of 1–20 min were more likely than no head injury comparisons to be impaired on measures of executive functioning and declarative memory. Impairments were evident when examining for single- and two-test impairment rates on measures of executive functioning and declarative memory.Conclusions: A subset of people that had reported a single mTBI with LOC more than 12 months ago may experience impairments in executive functioning and declarative memory, particularly those who spent more time unconscious.

Repeated mild traumatic brain injuries induce persistent changes in plasma protein and magnetic resonance imaging biomarkers in the rat

A single mild traumatic brain injury (mTBI) typically causes only transient symptoms, but repeated mTBI (RmTBI) is associated with cumulative and chronic neurological abnormalities. Clinical management of mTBI is challenging due to the heterogeneous, subjective and transient nature of symptoms, and thus would be aided by objective biomarkers. Promising biomarkers including advanced magnetic resonance imaging (MRI) and plasma levels of select proteins were examined here in a rat model of RmTBI. Rats received either two mild fluid percussion or sham injuries administered five days apart. Rats underwent MRI and behavioral testing 1, 3, 5, 7, and 30 days after the second injury and blood samples were collected on days 1, 7, and 30. Structural and diffusion-weighted MRI revealed that RmTBI rats had abnormalities in the cortex and corpus callosum. Proteomic analysis of plasma found that RmTBI rats had abnormalities in markers indicating axonal and vascular injury, metabolic and mitochondrial dysfunction, and glial reactivity. These changes occurred in the presence of ongoing cognitive and sensorimotor deficits in the RmTBI rats. Our findings demonstrate that RmTBI can result in chronic neurological abnormalities, provide insight into potential contributing pathophysiological mechanisms, and supports the use of MRI and plasma protein measures as RmTBI biomarkers.

Results of scoping review do not support mild traumatic brain injury being associated with a high incidence of chronic cognitive impairment: Commentary on McInnes et al. 2017.

A recently published review of 45 studies concluded that approximately half of individuals who sustain a single mild traumatic brain injury (MTBI) experience long-term cognitive impairment (McInnes et al. Mild Traumatic Brain Injury (mTBI) and chronic cognitive impairment: A scoping review. PLoS ONE 2017;12:e0174847). Stratified by age, they reported that 50% of children and 58% of adults showed some form of cognitive impairment. We contend that the McInnes et al. review used a definition of “cognitive impairment” that was idiosyncratic, not applicable to individual patients or subjects, inconsistent with how cognitive impairment is defined in clinical practice and research, and resulted in a large number of false positive cases of cognitive impairment. For example, if a study reported a statistically significant difference on a single cognitive test, the authors concluded that every subject with a MTBI in that study was cognitively impaired–an approach that cannot be justified statistically or psychometrically. The authors concluded that impairment was present in various cognitive domains, such as attention, memory, and executive functioning, but they did not analyze or report the results from any of these specific cognitive domains. Moreover, their analyses and conclusions regarding many published studies contradicted the interpretations provided by the original authors of those studies. We re-reviewed all 45 studies and extracted the main conclusions from each. We conclude that a single MTBI is not associated with a high incidence of chronic cognitive impairment.

Hypertension Exacerbates Cerebrovascular Oxidative Stress Induced by Mild Traumatic Brain Injury: Protective Effects of the Mitochondria-Targeted Antioxidative Peptide SS-31.

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

Auditory and Cognitive Behavioral Performance Deficits and Symptom Reporting in Postconcussion Syndrome Following Mild Traumatic Brain Injury.

Purpose This study examined auditory deficits and symptom reporting in individuals with long-term postconcussion symptoms following a single mild traumatic brain injury (mTBI) compared to age- and gender-matched controls without a history of mTBI. Method Case history interviews, symptom questionnaires, and a battery of central auditory and neuropsychological tests were administered to 2 groups. The mTBI group was a civilian population recruited from a local concussion management program who were seeking rehabilitation for postconcussion-related problems in a postacute period between 3 and 18 months following injury. Symptom validity testing was included to assess the rate of possible insufficient test effort and its influence on scores for all outcome measures. Analyses of group differences in test scores were performed both with and without the participants who showed insufficient test effort. Rates of symptom reporting, correlations among symptoms and behavioral test outcomes, and the relationships between auditory and cognitive test performance were analyzed. Results The mTBI group reported a high rate of auditory symptoms and general postconcussion symptoms. Performance on neuropsychological tests of cognitive function showed some differences in raw scores between groups, but when effort was considered, there were no significant differences in the rate of abnormal performance between groups. In contrast, there were significant differences in both raw scores and the rate of abnormal performance between groups for some auditory tests when only considering participants with sufficient effort. Auditory symptoms were strongly correlated with other general postconcussion symptoms. Conclusions Significant auditory symptoms and evidence of long-term central auditory dysfunction were found in a subset of individuals who had chronic postconcussion symptoms after a single mTBI unrelated to blast trauma. The rate of abnormal performance on auditory behavioral tests exceeded the rate of abnormal performance on tests of cognitive function. Supplemental Material https://doi.org/10.23641/asha.8329955.

Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats.

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Visualization of thalamic calcium influx with quantitative susceptibility mapping as a potential imaging biomarker for repeated mild traumatic brain injury

A key event in the pathophysiology of traumatic brain injury (TBI) is the influx of substantial amounts of Ca2+ into neurons, particularly in the thalamus. Detection of this calcium influx in vivo would provide a window into the biochemical mechanisms of TBI with potentially significant clinical implications. In the present work, our central hypothesis was that the Ca2+ influx could be imaged in vivo with the relatively recent MRI technique of quantitative susceptibility mapping (QSM). Wistar rats were divided into five groups: naive controls, sham-operated experimental controls, single mild TBI, repeated mild TBI, and single severe TBI. We employed the lateral fluid percussion injury (FPI) model, which replicates clinical TBI without skull fracture, performed 9.4 Tesla MRI with a 3D multi-echo gradient-echo sequence at weeks 1 and 4 post-injury, computed susceptibility maps using V-SHARP and the QUASAR-HEIDI technique, and performed histology. Sham, experimental controls animals, and injured animals did not demonstrate calcifications at 1 week after the injury. At week 4, calcifications were found in the ipsilateral thalamus of 25–50% of animals after a single TBI and 83% of animals after repeated mild TBI. The location and appearance of calcifications on stained sections was consistent with the appearance on the in vivo susceptibility maps (correlation of volumes: r = 0.7). Our findings suggest that persistent calcium deposits represent a primary pathology of repeated injury and that FPI-QSM has the potential to become a sensitive tool for studying pathophysiology related to mild TBI in vivo.

Cognitive and neuropsychiatric impairments vary as a function of injury severity at 12 months post-experimental diffuse traumatic brain injury: Implications for dementia development.

Traumatic brain injury (TBI) is a common risk factor for later neurodegeneration, which can manifest as dementia. Despite this, little is known about the time-course of development of functional deficits, particularly cognitive and neuropsychiatric impairments, and whether these differ depending on the nature of the initiating insult. Therefore, this study investigated long term functional impairment at 12 months post-injury following diffuse TBI of different severities. Male Sprague-Dawley rats (420-480 g; 10-12 weeks) were either given a sham surgery (n = 14) or subjected to Marmarou's impact acceleration model of diffuse TBI for a single mild TBI (n = 12), repetitive mild TBI (3 mild diffuse injuries at 5 day intervals) (n = 14) or moderate to severe TBI (n = 14). At 12 months after injury, they were tested on a functional battery encompassing motor, neuropsychiatric (anxiety and depressive-like) and cognitive function. Our results showed that moderate to severe TBI animals exhibited significant impairments in cognitive flexibility (p = 0.009) on the Barnes maze when compared to age-matched sham animals. Neither repetitive mild TBI nor single mild TBI animals showed significant functional impairments when compared to shams. Thus, this study provides the first insight into chronic functional impairments associated with different severities of diffuse TBI, with moderate to severe TBI being a higher risk factor for impaired cognitive function at 12 months post-injury. Taken together, this may have implications for risk of dementia development following different severities of injury.

Neurotoxic tau oligomers after single versus repetitive mild traumatic brain injury.

Mild traumatic brain injury accounts for the majority of head injuries and has been correlated with neurodegeneration and dementia. While repetitive mild traumatic brain injury is highly correlated to neurodegeneration, the correlation of a single mild traumatic brain injury with neurodegeneration is still unclear. Because tau aggregates are the main form of mild traumatic brain injury induced pathology, toxic forms of tau protein most likely play a role in the development of post-mild traumatic brain injury neurodegeneration. Therefore, it becomes crucial to characterize the properties of soluble tau aggregates in single versus repetitive mild traumatic brain injury. Herein, we isolated tau oligomers from wild-type mice exposed to single or repetitive mild traumatic brain injury and characterized the tau aggregates at functional, biochemical and biophysical levels. We demonstrated that single versus repetitive mild traumatic brain injuries frequencies lead to the formation of different tau oligomeric polymorphisms. These polymorphisms express different long-term potentiation impairment potencies, toxicity potentials, morphologies and strain indicating properties. To our knowledge, this is the first evidence that soluble tau oligomers derived from single versus repetitive mild traumatic brain injuries form distinct polymorphisms that possibly correlate with the risk of neurodegeneration after mild traumatic brain injury.

Single mild traumatic brain injury results in transiently impaired spatial long-term memory and altered search strategies.

Mild traumatic brain injury (mTBI) can lead to diffuse neurophysical damage as well as cognitive and affective alterations. The nature and extent of behavioral changes after mTBI are still poorly understood and how strong an impact force has to be to cause long-term behavioral changes is not yet known. Here, we examined spatial learning acquisition, retention and reversal in a Morris water maze, and assessed search strategies during task performance after a single, mild, closed-skull traumatic impact referred to as "minimal" TBI. Additionally, we investigated changes in conditioned learning in a contextual fear-conditioning paradigm. Results show transient deficits in spatial memory retention, which, although limited, are indicative of deficits in long-term memory reconsolidation. Interestingly, minimal TBI causes animals to relapse to less effective search strategies, affecting performance after a retention pause. Apart from cognitive deficits, results yielded a sub-acute, transient increase in freezing response after fear conditioning, with no increase in baseline behavior, an indication of a stronger affective reaction to aversive stimuli after minimal TBI or greater susceptibility to stress. Furthermore, western blot analysis showed a short-term increase in hippocampal GFAP expression, most likely indicating astrogliosis, which is typically related to injuries of the central nervous system. Our findings provide evidence that even a very mild impact to the skull can have detectable consequences on the molecular, cognitive and affective-like level. However, these effects seemed to be very transient and reversible.